Topical dermatological formulations and use thereof

ABSTRACT

A topical formulation of an androstane steroid compound of improved solubility in combinations of the solvents propylene glycol and propylene carbonate.

FIELD OF THE INVENTION

This invention relates to the field of topical formulations fordermatological uses wherein the formulation has enhanced solubility ofthe active dermatological agent in the formulation and the use thereofto treat dermatological conditions of a patient. More particularly, thisinvention relates to the field of topical formulations of androstanesteroids, and more particularly esters of fluticasone, fordermatological uses, such as anti-inflammatory and anti-allergic uses,wherein the formulation has enhanced solubility of the activedermatological agent in the formulation and the use thereof to treatdermatological conditions of a patient.

BACKGROUND TO THE INVENTION

Glucocorticosteroids, which have anti-inflammatory and anti-allergyproperties, are well known and are widely used to treat conditionsrequiring an anti-inflammatory and/or anti-allergic response. One suchclass of glucocorticosteroids having such properties are androstanesteroids of the type disclosed in U.S. Pat. No. 4,335,121, andparticularly fluticasone esters, and more particularly fluticasonepropionate, namely6α,9α-difluoro-17α(1-oxopropoxy)-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, and derivatives thereof. In this regard,CULTIVATE® topical cream and ointment, containing 0.05% and 0.005%fluticasone propionate respectively, is marketed by GlaxoSmithKline.These products have anti-inflammatory, anti-pruritic andvasoconstrictive properties.

It has been desirable to increase the activity of the active ingredientin such formulations. By increasing the vasoconstrictor potency, theeffectiveness of the active ingredient is increased. In InternationalPatent application Publication No. WO 00/24401 it is taught thatincreased vasoconstrictor potency of fluticasone propionate lotionformulations over fluticasone propionate cream formulations is obtainedat decreased concentrations of occlusive agent, i.e., under 10 w/w %.However, it is recognized that the addition of an occlusive agent, suchas mineral oil or paraffin, increases the vasoconstrictor potency oftopical steroids. Yet, high concentrations of occlusive agents can causethe formulation to be unstable, and invert an oil-in-water emulsion to agreasy feeling water-in-oil emulsion.

In order to still obtain the high vasoconstrictor potency of such a theformulation, while avoiding the instability problem of the product, andstill have a relatively high level of occlusive agent in the product, ithas been proposed in International patent Publication No. WO 02/13868,to employ a specific type of surfactant system, namely one wherein thesurfactant system employed in the formulation must have an HLB valueranging from about 7.0 to about 10.9 and with the surfactant systembeing present in the formulation in a w/w % amount of from about 0.25 toabout 10.0. Also, in United States Patent Application Publication Nos.2003/0130247 A1, 2003/0176408 A1 and 2003/0186951 A1 it is suggested toemploy very high amounts of a penetration enhancer, such as propyleneglycol, such that the ratio of the penetration enhancer to a total ofthe penetration enhancer, solvents and emulsifiers is at lest about0.70, preferably at least about 0.80 and most preferably about 0.90 or0.95, so as to obtain enhanced vasoconstriction activity or potency.However, it is desirable to be able to obtain such increased or evenbetter vasoconstriction potency for such androstane-containing topicalformulations without the necessity for using such high levels ofpenetration enhancers.

Thus, there is still a need for better, more reliable topicalformulations where the amount of active ingredient available forvasoconstrictor activity is increased and without requiring unduelimitations on the compositions of the formulations. Hence, there is aneed for such topical formulation where the amount of active ingredientsoluble in the solvent system of the formulation is increased andthereby the vasoconstrictor activity or potency of the formulation isincreased.

BRIEF SUMMARY OF THE INVENTION

In accordance with the present invention, topical formulations ofandrostane steroid compounds having increased solubility of theandrostane steroid compound in the formulation solvent system isobtained when the solvent system comprises both propylene glycol andpropylene carbonate. Thus, the topical formulations of this inventionwill be a stable formulation comprising an androstane steroid compoundin a solvent system comprising both propylene glycol and propylenecarbonate. Unexpectedly, it has been discovered that the combination ofpropylene glycol and propylene carbonate provides a synergisticenhancement of the solubility of the androstane steroid compound in thesolvent system. Thus, the formulation provides increased amount of theandrostane steroid compound available for vasoconstrictor potency oractivity and thereby increased effectiveness of the formulation intreating the dermatological conditions for which the formulation isapplied to a patient in need thereof. The androstane steroid compound inthe formulation of this invention is a compound of the formula:

where R¹ is a fluoro-, chloro-, bromo-methyl group or a 2′-fluoromethylgroup; R² is a group COR⁶ where R⁶ is a C₁₋₃ alkyl group or OR² and R³together form a 16α,17α-isopropylidenedioxy group; R³ is a hydrogenatom, a methyl group (which may be either the α- or β-configuration) ora methylene group; R⁴ is hydrogen, chlorine or fluorine atom; and R⁵ isa hydrogen or fluorine atom, and the symbol -- represents a single ordouble bond.

The invention additionally provides a process for topically treating askin condition of a patient including but not limited to the followingconditions, corticosteroid-responsive dermatoses, such as atropicdermatitis, eczema, including atopic, infantile, and disco eczemas,purigo nodularis; neurodermatoses, including lichen simplex, lichenplanus, seborrhoeic dermatitis; contact sensitivity reactions; discoidpupus erthematosus; insect bite reactions; prickly heat; inflammation,erythema, papulation, scaling erosion, oozing, crusting, pruritus,impetigo, epidermolysis bullosa, psoriasis, erythema, hidradentis,suppurative warts, diaper rash, jock itch, and combinations of theseconditions. The method comprises topically applying a formulation ofthis invention, as described hereinbefore and hereafter, to a patient inneed of the treatment for such a condition. The formulation of thisinvention will be a topical formulation, generally in a cream or lotion,ointment, or gel form,

A further aspect of this invention is a process for the preparation ofsuch formulation of this invention by mixing the androstane steroidactive ingredient with the two solvents, propylene glycol and propylenecarbonate, and other components of the system including, but not limitedto, components such as surfactant(s), stiffening or thickening agent(s),wax(es) as occlusive agent(s), emollient(s), penetration enhancer(s),preservative(s), base(s), and water or buffer, and the like.

BRIEF SUMMARY OF THE DRAWINGS

The invention is illustrated, in part, but not limited by the drawingsin which:

the FIGURE is a graph of the theoretical (idealized) and actualsolubility of fluticasone propionate in propylene glycol and propylenecarbonate and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In accordance with the present invention, topical formulations ofandrostane steroid compounds having increased solubility of theandrostane steroid compound in the formulation solvent system isobtained when the solvent system comprises both propylene glycol andpropylene carbonate. Thus, the topical formulations of this inventionwill be a stable formulation comprising an androstane steroid compoundin a solvent system comprising both propylene glycol and propylenecarbonate. Unexpectedly, it has been discovered that the combination ofpropylene glycol and propylene carbonate provides a synergisticenhancement of the solubility of the androstane steroid compound in thesolvent. Thus, the formulation provides increased amount of theandrostane steroid compound available for vasoconstrictor activity orpotency and thereby increased effectiveness of the formulation intreating the dermatological conditions for which the formulation isapplied to a patient in need thereof. The androstane steroid compound inthe formulation of this invention is a compound of the formula:

where R¹ is a fluoro-, chloro-, bromo-methyl group or a 2′-fluoromethylgroup; R² is a group COR⁶ where R⁶ is a C₁₋₃ alkyl group or OR² and R³together form a 16α,17α-isopropylidenedioxy group; R³ is a hydrogenatom, a methyl group (which may be either the α- or β-configuration) ora methylene group; R⁴ is hydrogen, chlorine or fluorine atom; and R⁵ isa hydrogen or fluorine atom, and the symbol -- represents a single ordouble bond.

The invention additionally provides a process for topically treating askin condition of a patient including but not limited to the followingconditions, corticosteroid-responsive dermatoses, atopic dermatitis,inflammation, eczema, erythema, papulation, scaling erosion, oozing,crusting, pruritus, impetigo, epidermalysis bullosa, psoriasis,erythema, hidradenitis, suppurative warts, diaper rash, jock itch, andcombinations of these conditions. The method comprises topicallyapplying a formulation of this invention, as described hereinbefore andhereafter, to a patient in need of the treatment for such a condition.

A further aspect of this invention is a process for the preparation ofsuch formulation of this invention by mixing the androstane steroidactive ingredient with the two solvents, propylene glycol and propylenecarbonate, and other components of the system including, but not limitedto, components such as surfactant(s), stiffening or thickening agent(s),wax(es) as occlusive agent(s), emollient(s), penetration enhancer(s),preservative(s), base(s) and water or buffer, and the like.

The androstane steroid active ingredient in the topical formulations ofthis invention is a fluticasone compound or a pharmaceuticallyacceptable salt or ester thereof. The active ingredient will be presentin the topical formulations of this invention in a w/w % amount of fromabout 0.05 to about 0.50%, preferably from about 0.05 to 0.20%, forcream or lotion and gel formulations, and for ointment formulations theactive ingredient w/w % will generally be from about 0.005 to about0.50% preferably from about 0.005 to 0.20%. The cream and lotionformulations are oil-in-water emulsions, and the ointments arenon-aqueous dispersions in a base. Suitable androstane steroid compoundsuseful as the active ingredient in the formulations of this inventionare compounds of the formula:

where R¹ is a fluoro-, chloro-, bromo-methyl group or a 2′-fluoromethylgroup; R² is a group COR⁶ where R⁶ is a C₁₋₃ alkyl group or OR² and R³together form a 16α,17α-isopropylidenedioxy group; R³ is a hydrogenatom, a methyl group (which may be either the α- or β-configuration) ora methylene group; R⁴ is hydrogen, chlorine or fluorine atom; and R⁵ isa hydrogen or fluorine atom, and the symbol -- represents a single ordouble bond. The preferred active ingredient is flucatisone propionate.

The solvent system of this invention comprises both propylene glycol andpropylene carbonate. The use of both propylene glycol and propylenecarbonate as solvents in accordance with this invention permitssynergistically increased solubility of the active ingredient in thetopical formulations and thereby provides increased vasoconstrictorpotency of the formulation based on a given amount of active ingredientin the formulation. The amount of propylene glycol employed in theformulations of this invention will generally be a w/w % amount of fromabout 2.5 to about 35%. For ointment formulations of this invention theamount of propylene glycol solvent will generally be from about 2.5 toabout 7.5 w/w %, for cream or lotion formulations of this invention willgenerally be from about 2.5 to about 20 w/w %, and for gel formulationof this invention will generally be from about 2.0 to about 35 w/w %.The amount of propylene carbonate employed in the formulations of thisinvention will generally be a w/w % amount of from about 2.0 to about20%. For ointment formulations of this invention the amount of propylenecarbonate solvent will generally be from about 2.5 to about 7.5 w/w %,for cream or lotion formulations of this invention will generally befrom about 2.5 to about 15 w/w %, and for gel formulations of thisinvention will generally be from about 2.0 to about 20 w/w %. The weightratio of propylene carbonate to propylene glycol will generally be fromabout 99:1 to about 1:99, preferably from about 99:5 to about 5:99, morepreferably about 99:1 to about 40:60, and still more preferably fromabout 88:12 to about 45:55, and even more preferably about 88:12.

The topical formulations of this invention may contain a number of othercomponents, including but not limited to, components such assurfactant(s), stiffening or thickening agent(s), wax(es) as occlusiveagent(s), emollient(s), penetration enhancer(s), preservative(s),base(s) and water or buffer(s), and the like.

Any suitable compatible surfactant(s) may be employed in the topicalformulations of this invention. Examples of such surfactants include,but are not limited to ceteareth-20 available as CETOMACROGOL® 1000,glycerol monostearate, glycerol distearate, glyceryl stearate,polyoxyethylene stearate, a blend of glyceryl stearate and PEG-100stearate, (As ArLACEL 1 65), polysorbate 40, polysorbate 60, polysorbate80, CETETH-20®, sorbitan monopalmitate, sorbitan monostearate, sorbitanmonooleate, sorbitan sesquioleate, and mixtures thereof. The amount ofsurfactant(s) employed in the formulations of this invention willgenerally be in a w/w % of from about 0.5 to about 10%. Generally forthe ointment formulations of this invention the amount of surfactant(s)will generally be from about 0.5 to about 5.0 w/w %, and for the creamformulations of this invention the amount of surfactant(s) will be fromabout 1.0 to about 10 w/w %.

Any suitable occlusive agent may be employed in the topical formulationsof this invention. Suitable occlusive agent include, but are not limitedto, petrolatum, microcrystalline wax, beeswax, mineral oil, squalene,liquid paraffin, shea butter, carnauba wax, SEPIGEL® (a blend ofisoparrafin/polyacrylamide/laureth-7), and mixtures thereof. Theocclusive agent is preferably a wax and is present in the formulationsof this invention in a w/w % amount of from about 5.0 to about 30%. Forthe ointment formulations of this invention the occlusive agent or waxcomponent will generally be employed in the formulation in an amount offrom about 20 to a bout 30 w/w %, and for cream or lotion formulationsof this invention in an amount of from about 5.0 to about 20 w/w %.

Any suitable emollient or skin conditioning agent may optionally beincluded in the topical formulations of this invention. Suitableemollients include, but are not limited to, cholesterol, glycerine,glyceryl monostearate, isopropyl myristate, isopropyl palmitate,cetostearyl alcohol, lanolin alcohols and mixtures thereof. Optionally,dimethicone, mineral oil or white soft paraffin may also be incorporatedinto the formulations in relatively small amounts to act as a skinconditioner. The emollient or skin conditioning agent may be present inthe topical formulations of this invention in a w/w % amount of fromabout 0.0 to about 40%. In the ointment formulations of this inventionthe emollient or skin conditioning agent may generally be present in anamount of from about 0.0 to about 10 w/w %, and in the cream or lotionformulations of this invention may generally be present in an amount offrom about 2.0 to about 40.0 w/w %.

The formulations of this invention may also optionally contain anysuitable penetration enhancer. Suitable penetration enhancers include,but are not limited to, diethylene glycol, monoethyl ether, n-decylmethyl sulfoxide, dimethyl sulfoxide, dimethylacetamide, laurocapram(Azone®), dimethylformamide, sucrose monooleate, andN-methyl-2-pyrrolidine (Pharmasolve®). The penetration enhancer may bepresent in the formulations of this invention in an amount of from about0.0 to about 5.0 w/w %. In the ointment formulations of this inventionthe penetration enhancer may generally be present in an amount of fromabout 0.0 to about 5 w/w %, and in the cream or lotion formulations ofthis invention may generally be present in an amount of from about 0.0to about 5 w/w %.

The formulations of this invention may also optionally include a bufferor neutralizing agent. Examples of suitable buffers include, but are notlimited to, citric acid, lactic acid, oleic acid, sodium phopsphate,water, triethanolamine, sodium citrate, hydrochloric acid and the like.The buffering agent may be present in the composition in any suitablebuffering effective a mount. The gel formulation will generally containa base, such as for example, sodium hydroxide, triethanolamine and thelike. The gel formulations of this invention will also generally includea volatile solvent, such as for example, ethanol, isopropanol and thelike.

The formulations of this invention may also optionally includepreservative or antioxidant components. Examples of such preservativeand antioxidant include, but are not limited to, alkyl alcohols, benzylalcohol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, disodium edetate, citric acid and the like. The preservativeand/or antioxidant may be present in the formulations of this inventionin a w/w amount of from about 0.0 to about 0.6%, preferably in an amountof from about 0.3 to about 0.6%.

The formulations of this invention optionally may also have present inthe formulations thickening or stiffening agent, including but notlimited to, dimethicone and polymers. The thickening or stiffeningagents may be present in the composition generally in a w/w % amount offrom about 0.0 to 10%, preferably from about 0.1 to about 10%, and morepreferably in an amount of from about 0.1 to 5%.

Typically ointment formulations of this invention will generally havethe following composition components, in the amount indicated.

General Ointment Formulation: Component Approximate Amount (% w/w)Androstane steroid 0.005 to 0.1  Propylene 2.5 to 7.5 carbonate¹Propylene glycol¹ 2.5 to 15  Surfactant 0.5 to 1.0 Wax 20 to 30Emollient 0.0 to 10  Penetration 0.0 to 5.0 enhancer Mineral oil Q.s.¹The sum of these components is ≦10% w/w.The androstane steroid is preferably fluticasone propionate.

The ointment formulation will generally be prepared in the followingmanner. The steroid active ingredient, i.e., fluticasone propionate,will be solubilized in a mixture of propylene carbonate and propyleneglycol. The total amount of solvent in these ointment formulations islikely to be 10% w/w or less. This solution will be dispersed in an oilbase containing a surfactant and wax. The wax may be a single componentor a combination of waxes with different physical properties.Optionally, the formulation may contain an emollient and a penetrationenhancer.

Examples of specific ointment formulations of this invention are thefollowing compositions. In these exemplary compositions fluticasonepropionate is used as an exemplary androstane steroid, however, it willbe recognized that the compositions may contain any androstane steroid.

OINTMENT FORMULATION EXAMPLE 1

Component Amount (% w/w) Fluticasone 0.1 propionate Propylene carbonate5.0 Propylene glycol 5.0 Sorbitan sesquioleate 1.0 Microcrystalline wax20 Isopropyl myristate 5.0 Oleic acid 2.5 Mineral oil Q.s.

OINTMENT FORMULATION EXAMPLE 2

Component Amount (% w/w) Fluticasone 0.05 propionate Propylene carbonate2.5 Propylene glycol 2.5 Sorbitan sesquioleate 0.5 Microcrystalline wax20 Isopropyl myristate 5.0 Oleic acid 2.5 Mineral oil Q.s.

OINTMENT FORMULATION EXAMPLE 3

Component Amount (% w/w) Fluticasone 0.1 propionate Propylene carbonate5.0 Propylene glycol 1.7 Sorbitan sesquioleate 0.75 Beeswax 25 Oleicacid 2.5 Mineral oil Q.s.

OINTMENT FORMULATION EXAMPLE 4

Component Amount (% w/w) Fluticasone propionate 0.05 Propylene carbonate2.5 Propylene glycol 7.5 Sorbitan sesquioleate 1.0 Microcrystalline wax,65° C.¹ 15 Microcrystalline wax, 75° C.¹ 10 Isopropyl myristate 2.5Oleic acid 2.5 Mineral oil Q.s.¹Approximate melting point

Further ointment compositions of this invention include, for example,the following compositions, in which the amount of the components are wt%. Ointment Ointment Ointment Ointment Component 5 6 7 8 Fluticasonepropionate 0.05 0.02 0.075 0.1 Microcrystalline Wax 30 30 30 15 Sorbitansesquioleate 1.5 2 3 3.0 Glycerol monostearate 1.5 1.5 1.5 1.5 Oleicacid 2.5 1 2.5 2.5 Butylated 0.05 0.05 0.05 0.05 hydroxytoluenePropylene glycol 0.825 3.15 1.25 3.0 Propylene carbonate 2.475 1.05 3.754.5 Mineral oil 61.1 61.23 57.875 Q.s. Beeswax — — — 15

Typical cream formulation of this invention will generally have thefollowing components in the amounts indicated.

General Cream Formulation: Component Approximate Amount (% w/w)Androstane steroid 0.05 to 0.20 Propylene carbonate¹ 2.5 to 15 Propylene glycol¹ 2.5 to 20  Surfactant 1.0 to 10  Stiffening agent(s)0.1 to 14  Waxes 5.0 to 20  Emollient(s) 2.0 to 40  Penetration enhancer0.0 to 5.0 Mineral oil 0.0 to 5.0 Preservatives 0.3 to 0.6 Polymer   0.0 to 5.0% Base    0.0 to 5.0% Water (buffer) Q.s.¹The sum of these components is ≦35% w/wThe androstane steroid is preferably fluticasone propionate.

The cream formulations of this invention will generally be prepared inthe following manner. Micronized fluticasone propionate will still bedispersed as fine particles in an oil-in-water cream base that containspropylene carbonate and propylene glycol. The total amount of solvent inthese cream formulations is likely to be 35% w/w or less. Optionally,the formulation may contain a penetration enhancer. Drug concentrationin the formulation would range from about 0.05 to about 15% w/w.

Exemplary cream formulations of this invention include the followingcompositions. In these exemplary compositions fluticasone propionate isused as an exemplary androstane steroid, however, it will be recognizedthat the compositions may contain any androstane steroid.

CREAM FORMULATION EXAMPLE 1

Component Approximate Amount (% w/w) Fluticasone 0.15 propionatePropylene carbonate 8.0 Propylene glycol 10 Cetomacrogol ® 1000 2.1Glycerol monostearate 0.9 Cetosterayl alcohol 4.0 Beeswax 8.0 Isopropylpalmitate 22.0 Oleic acid 2.5 Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 2

Component Approximate Amount (% w/w) Fluticasone 0.1 propionatePropylene carbonate 5.0 Propylene glycol 5.0 Arlacel ® 165 2.5Polysorbate 60 0.5 Cetosterayl alcohol 4.0 Cetyl esters wax 5.0Isopropyl myristate 20 Oleic acid 2.5 Mineral oil 1.0 Dimethicone 1.0Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 3

Component Approximate Amount (% w/w) Fluticasone 0.1 propionatePropylene carbonate 5.0 Propylene glycol 10 Cetomacrogol ® 1000 2.1Glycerol monostearate 0.9 Cetosterayl alcohol 3.0 Beeswax 8.0 Isopropylpalmitate 22.0 Oleic acid 5.0 Parabens/Imidurea 0.5 Carbomer 974 0.5Triethanolamine 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 4

Component Approximate Amount (% w/w) Fluticasone 0.1 propionatePropylene carbonate 10 Propylene glycol 5 Cetomacrogol ® 1000 2.1Glycerol monostearate 0.9 Cetosterayl alcohol 3.0 Beeswax 8.0 Cetyl waxesters Isopropyl myristate 20.0 Oleic acid 1.0 Parabens/Imidurea 0.5Carbomer 974 0.5 Sodium hydroxide 0.25 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 5

Component Approximate Amount (% w/w) Fluticasone 0.15 propionatePropylene carbonate 8.0 Propylene glycol 10 Polysorbate 60 1.0Cetosterayl alcohol 4.0 Microcrystalline wax 5.0 Isopropyl palmitate 5.0Oleic acid 5.0 Mineral oil 10 Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 6

Component Approximate Amount (% w/w) Fluticasone 0.1 propionatePropylene carbonate 5.0 Propylene glycol 5.0 Polysorbate 60 1.0Cetosterayl alcohol 4.0 Cetyl esters wax 5.0 Isopropyl palmitate 5.0Oleic acid 2.5 Mineral oil 20 Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 7

Component Approximate Amount (% w/w) Fluticasone 0.1 propionatePropylene carbonate 5.0 Propylene glycol 10 Polysorbate 60 2.0Cetosterayl alcohol 8.0 Microcrystalline wax 9.0 Dimethicone 5.0 Oleicacid 5.0 Mineral oil 10 Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 8

Component Approximate Amount (% w/w) Fluticasone 0.15 propionatePropylene carbonate 8.0 Propylene glycol 5.0 Glycerol monostearate 3.0Cetosterayl alcohol 8.0 Microcrystalline wax 5.0 Isopropyl palmitate 5.0Oleic acid 5.0 Mineral oil 10 Parabens/Imidurea 0.5 Water (buffer) Q.s.

CREAM FORMULATION EXAMPLE 9

Component % w/w Fluticasone 0.1 propionate Beeswax 10 Isopropylpalmitate 20 Oleic acid 1 Dimethicone 20 cs 1 Cetostearyl alcohol 3Glycerol 2.1 monostearate Cetomacrogol 1000 0.9 Propylene glycol 5Propylene carbonate 5 Imidurea 0.2 Methyl paraben 0.2 Propyl paraben 0.1Carbopol 947P 0.5 5% NaOH 2 Water Q.s.

CREAM FORMULATION EXAMPLE 10

Component % w/w) Fluticasone propionate 0.2 Propylene carbonate 7.5Propylene glycol 15 Cetomacrogol ® 1000 2.1 Glycerol monostearate 0.9Cetosterayl alcohol 3.0 Beeswax 15 Dimethicone 0.5 Isopropyl palmitate7.5 Isopropyl myristate 7.5 Oleic acid 1.0 BHT 0.05 Parabens/Imidurea0.35 Carbomer 974 0.5 Sodium hydroxide 0.15 Water (buffer) Q.s.

Typical gel formulations of this invention will generally have thefollowing composition components in the amounts indicated.

General Gel Formulation Component Approximate Amount (% w/w) Fluticasone0.05 to 0.2 propionate Propylene carbonate 2.0 to 35  Propylene glycol2.0 to 20  Polymer 0.1 to 5.0 Base    0.0 to 5.0% Volatile solvent²  0.0 to 30% Water (buffer) Q.s.

Examples of specific gel formulations of this invention are thefollowing gel compositions. In these exemplary compositions fluticasonepropionate is used as the exemplary androstane steroid, however, it isto be recognized that the composition can contain any androstanesteroid.

GEL FORMULATION EXAMPLE 1

Component Approximate Amount (% w/w) Fluticasone 0.2 propionatePropylene carbonate 7 Propylene glycol 15 Carbomer 974 0.5 Sodiumhydroxide 0.25 Water (buffer) Q.s.

GEL FORMULATION EXAMPLE 2

Component Approximate Amount (% w/w) Fluticasone propionate 0.25Propylene carbonate 10 Propylene glycol 25 Hydroxypropylcellulose 0.5Ethanol 20 Water (buffer) Q.s.

GEL FORMULATION EXAMPLE 3

Component Approximate Amount (% w/w) Fluticasone propionate 0.25Propylene carbonate 10 Propylene glycol 30 Oleic acid 5.0Hydroxypropylcellulose 2.5 Ethanol 20 Water (buffer) Q.s.

The unexpected solubility of the androstane steroid compounds in thecombined solvents propylene glycol and propylene carbonate isillustrated by the following solubility data and the solubility graph inFIG. 1 showing the expected idealized or theoretical solubility and theunexpectedly improved solubility actually obtained with the solventcombination of this invention at 25° C. The following Table shows theactual solubility of fluticasone propionate in mixtures of propyleneglycol and propylene carbonate. TABLE % propylene glycol/ Fluticasonepropionate solubility % propylene carbonate (% w/w) 100/0  0.08 75/250.48 50/50 1.09 25/75 1.56 12.5/87.5 1.72  0/100 1.17

In the drawing FIGURE this solubility data obtained at 25° C. is plottedas the dark line and the idealized (theoretical) solubility is plottedas the light line. In “ideal” solutions, the effect of each component isadditive in a linear fashion. If solvent A has a property with a valueof 50 and solvent B a value of 100 for the same property, an equal blendof A and B would be expected to give a value of 75 for that property.The solubility data obtained with the mixture of propylene glycol andpropylene carbonate shows that there is a synergistic solubility effectobtained with this combination of solvents. The lightly colored linerepresents “ideal” linear behavior. Since propylene glycol cansolubilize about 10 times more drug than propylene carbonate, the“ideal” line slopes down strongly as we move from pure propylene glycolto pure propylene carbonate. The darkly colored line shows the actualmeasured values of fluticasone propionate solubility in the blends. Twoimportant observations can be made. First, for all mixtures, themeasured solubility exceeds the ideal solubility. Second, for blendscontaining about 99 to 45% propylene carbonate, the measured solubilityexceeds the solubility in propylene glycol. Both observations arevaluable to the formulator because they show that more drug can beincorporated than predicted from the individual contributions of eachsolvent.

While the invention has been described herein with reference to thespecific embodiments thereof, it will be appreciated that changes,modification and variations can be made without departing from thespirit and scope of the inventive concept disclosed herein. Accordingly,it is intended to embrace all such changes, modification and variationsthat fall with the spirit and scope of the appended claims.

1. A composition for topical administration comprising an androstanesteroid compound in a formulation having both propylene glycol andpropylene carbonate solvents.
 2. A composition according to claim 1wherein the androstane steroid is a compound of the formula:

where R¹ is selected from the group consisting of a fluoro-, chloro-,bromo-methyl group or a 2′-fluoromethyl group; R² is a group COR⁶ whereR⁶ is selected from the group consisting of a C₁₋₃ alkyl group or OR²and R³ together form a 16α,17α-isopropylidenedioxy group; R³ is selectedfrom the group consisting of a hydrogen atom, a methyl group and amethylene group; R⁴ is selected from the group consisting of a hydrogen,chlorine and fluorine atom; and R⁵ is selected from the group consistingof a hydrogen and a fluorine atom, and the symbol -- represents a singleor double bond.
 3. A composition according to claim 1 wherein theandrostane steroid compound is fluticasone propionate.
 4. A compositionaccording to claim 1 wherein the weight ratio of ratio of propylenecarbonate to propylene glycol in the composition is from about 99:5 toabout 5:99.
 5. A composition according to claim 1 wherein the weightratio of ratio of propylene carbonate to propylene glycol in thecomposition is from about 88:12 to about 45:55.
 6. A compositionaccording to claim 1 wherein the weight ratio of ratio of propylenecarbonate to propylene glycol in the composition is about 88:12.
 7. Acomposition according to claim 3 wherein the weight ratio of ratio ofpropylene carbonate to propylene glycol in the composition is from about99:5 to about 5:99.
 8. A composition according to claim 3 wherein theweight ratio of ratio of propylene carbonate to propylene glycol in thecomposition is from about 88:12 to about 45:55.
 9. A compositionaccording to claim 3 wherein the weight ratio of ratio of propylenecarbonate to propylene glycol in the composition is about 88:12.
 10. Acomposition according to claim 1 wherein the composition is an ointment.11. A composition according to claim 1 wherein the composition is acream or lotion.
 12. A composition according to claim 3 wherein thecomposition is an ointment.
 13. A composition according to claim 3wherein the composition is a cream or lotion.
 14. A compositionaccording to claim 1 which is an ointment and comprising on aweight/weight basis Component Amount (% w/w) Androstane steroid 0.005 to0.1  Propylene carbonate¹ 2.5 to 7.5 Propylene glycol 2.5 to 7.5Surfactant 0.5 to 1.0 Wax 20 to 30 Emollient 0.0 to 10  Penetrationenhancer 0.0 to 5.0 Mineral oil Q.s.

and the total of the propylene glycol and propylene carbonate componentsis about 10% or less.
 15. The composition according to claim 14 whereinthe androstane steroid is fluticasone propionate.
 16. The compositionaccording to claim 1 which is a cream or lotion and comprising on aweight/weight basis Component Amount (% w/w) Androstane steroid  0.05 to0.20 Propylene carbonate 2.5 to 10 Propylene glycol 2.5 to 10 Surfactant1.0 to 10 Stiffening agent(s) 0.1 to 14 Waxes 5.0 to 20 Emollient(s) 2.0to 40 Penetration enhancer  0.0 to 5.0 Mineral oil  0.0 to 5.0Preservatives  0.3 to 0.6 Polymer     0.0 to 5.0% Base     0.0 to 5.0%Water (buffer) Q.s.

and the total of the propylene glycol and propylene carbonate componentsis about 35% or less.
 17. A composition according to claim 16 whereinthe androstane steroid comprises fluticasone propionate.
 18. Acomposition according to claim 1 additionally comprising one or more ofthe following components surfactant(s), stiffening or thickeningagent(s), wax(es), occlusive agent(s), emollient(s), penetrationenhancer(s), preservative(s), base(s), and water or buffer,
 19. Acomposition according to claim 18 wherein the androstane steroid isfluticasone propionate.
 20. A composition according to claim 1comprising an ointment having on a w/w % basis Component Approximate %Fluticasone 0.05 propionate Microcrystalline 30 Wax Sorbitan 1.5sesquioleate Glycerol 1.5 monostearate Oleic acid 2.5 Butylated 0.05hydroxytoluene Propylene 0.825 glycol Propylene 2.475 carbonate Mineraloil 61.1

and the total of the propylene glycol and propylene carbonate componentsis about 10% or less.
 21. A composition according to claim 1 comprisingan ointment having on a weight/weight basis Component Approximate w/w %Fluticasone 0.02 propionate Microcrystalline 30 Wax Sorbitan 2sesquioleate Glycerol 1.5 monostearate Oleic acid 1 Butylated 0.05hydroxytoluene Propylene 3.15 glycol Propylene 1.05 carbonate Mineraloil 61.23


22. A composition according to claim 1 comprising an ointment having ona wt/wt basis Component Approximate w/w % Fluticasone 0.075 propionateMicrocrystalline 30 Wax Sorbitan 3 sesquioleate Glycerol 1.5monostearate Oleic acid 2.5 Butylated 0.05 hydroxytoluene Propylene 1.25glycol Propylene 3.75 carbonate Mineral oil 57.875


23. A method for treating a skin condition, the process comprisingtopically applying to the skin a composition comprising an androstanesteroid compound in a formulation having both propylene glycol andpropylene carbonate solvents.
 24. A method according to claim 23 whereinthe androstane steroid is a compound of the formula:

where R¹ is selected from the group consisting of a fluoro-, chloro-,bromo-methyl group or a 2′-fluoromethyl group; R² is a group COR⁶ whereR⁶ is selected from the group consisting of a C₁₋₃ alkyl group or OR²and R³ together form a 16α,17α-isopropylidenedioxy group; R³ is selectedfrom the group consisting of a hydrogen atom, a methyl group and amethylene group; R⁴ is selected from the group consisting of a hydrogen,chlorine and fluorine atom; and R⁵ is selected from the group consistingof a hydrogen and a fluorine atom, and the symbol -- represents a singleor double bond.
 25. A method according to claim 24 wherein theandrostane steroid is fluticasone propionate.
 26. A method according toclaim 24 wherein composition is an ointment comprising on aweight/weight basis Component Approximate w/w % Androstane steroid 0.005to 0.1  Propylene carbonate¹ 2.5 to 7.5 Propylene glycol 2.5 to 7.5Surfactant 0.5 to 1.0 Wax 20 to 30 Emollient 0.0 to 10  Penetrationenhancer 0.0 to 5.0 Mineral oil Q.s.


27. A method according to claim 26 wherein the androstane steroid isfluticasone propionate
 28. A method according to claim 24 wherein thecomposition is a cream or lotion and comprising on a weight/weight basisComponent Approximate w/w % Androstane steroid  0.05 to 0.15 Propylenecarbonate 2.5 to 15 Propylene glycol 2.5 to 20 Surfactant 1.0 to 10Stiffening agent(s) 0.1 to 10 Waxes 5.0 to 20 Emollient(s) 2.0 to 40Penetration enhancer  0.0 to 5.0 Mineral oil  0.0 to 5.0 Preservatives 0.3 to 0.6 Polymer     0.0 to 5.0% Base     0.0 to 5.0% Water (buffer)Q.s.

and the total of the propylene glycol and propylene carbonate componentsis about 35% or less.
 29. A method according to claim 28 wherein theandrostane steroid is fluticasone propionate.
 30. A method according toclaim 24 wherein the skin condition is selected from the groupconsisting of corticosteroid-responsive dermatoses, atopic dermatitis,inflammation, eczema, erythema, papulation, scaling erosion, oozing,crusting, pruritus, impetigo, epidermolysis bullosa, psoriasis,erythema, hidradenitis, suppurative warts, diaper rash, jock itch, andcombinations of these conditions.